Mikanolide derivatives, their preparation and therapeutic uses

ABSTRACT

The invention concerns novel mikanolide derivatives, their preparation method and their therapeutic uses, in particular as anti-cancer and anti-viral agents. The compounds correspond to general formula (1) corresponding to general sub-formulae (I) 1  and (I) 2 , wherein: R 1  represents H, SR 4  or NR 4 R 5 ; R 2  represents SR 6  or NR 6 R 7 ; R 3  represents OH, O(CO)R 14 , OSiR 15 R 16 R 17 , O(CO)OR 18  or O(CO)NHR 18 , each of the radicals R 4 , R 6 , R 15 , R 16  and R 17  representing independently (in particular) an alkyl radical, the radicals R 5  and R 7  representing (in particular) radicals selected independently among a hydrogen atom and an alkyl radical, and each of the radicals R 14  and R 18  representing independently (in particular) an alkyl or cycloalkyl radical, or one among aryl, heteroaryl, aralkyl or heteroalkyl radicals optionally substituted; provided that when the compounds correspond to the general sub-formula (I) 2 , then R 1  does not represent a hydrogen atom.

[0001] A subject of the invention is new derivatives of mikanolide,their preparation processes as well as their therapeutic uses, inparticular as anticancerous, antibacterial and antiviral agents.

[0002] Tropical plants of the Mikania genus such as M. cordata, M.scandens or M. micrantha are part of certain traditional pharmacopeia ofIndia, South America and Central America. Under the names of guaco,bejuco de finca, cepu, liane francois, matafinca, or also vedolin, theextracts of Mikania are used as antibiotics and anti-inflammatories.

[0003] Active substances originating from extracts of Mikania have beenisolated and characterized: these are mikanolide and dihydromikanolide(see their structures in the figure below), and to a lesser extentscandenolides. These are sesquiterpenes of the germacrane family, i.e.having 4-isopropyl-1,7-dimethylcyclodecane as a hydrocarbon skeleton(Herz et al., Tetrahedron Lett. (1967) 3111-3115; Kiang et al.,Phytochemistry (1968) 7: 1035-1037; Cuenca et al., J. Nat. Prod. (1988),51, 625-626).

[0004] Studies of the extracts of Mikania report an antimicrobialactivity against Staphylococus aureus and Candida albicans (Facey etal., J. Pharm. Pharmacol. (1999) 51, 1455-1460; Mathur et al., Rev.Latinoam. Quim. (1975), 6, 201-205). Molluscicidal, piscicidal andbactericidal activities have also been described for dihydromikanolide(Vasquez et al., A G Meeting, Amsterdam, Netherlands, Jul. 26-30 , 1999,poster No. 316).

[0005] For the purpose of elucidating structures, certain simplederivatives of mikanolide and dihydromikanolide, and in particular thecompounds of general formulae (A1) and (A2) represented below

[0006] in which R represents a hydrogen atom or the acetyl group, havebeen synthesized and described in Herz et al., J. Org. Chem. (1970), 35,1453-1464. However, no pharmacological activity has been disclosed forthese compounds.

[0007] The Applicant recently described in PCT Patent Application WO01/39720 that mikanolide and dihydromikanolide are endowed with anantiproliferative activity linked to the inhibition of DNA-polymerase.However, mikanolides do not possess all the physico-chemical propertiesdesirable for medicamentous use as they are neither very water soluble,nor very stable, which renders their pharmaceutical use relativelydifficult, in particular in injectable form.

[0008] The Applicant has now developed new semi-synthetic mikanolidederivatives, which can be used for the treatment of diseases due toabnormal cell proliferation, in particular for the treatment of cancer,viral diseases and bacterial and parasitic infections. These compoundshave the advantage of better solubility and better stability than thatof mikanolide and dihydromikanolide while retaining an activity similarto or even greater than that of the latter.

[0009] A subject of the invention is the compounds of general formula(I)

[0010] corresponding to general sub-formulae (I)₁ and (I)₂

[0011] in which

[0012] R₁ represents a hydrogen atom or an SR₄ or NR₄R₅ radical;

[0013] R₂ represents SR₆ or NR₆R₇;

[0014] R₃ represents OH, O(CO)R₁₄, OSiR₁₅R₁₆R₁₇, O(CO)OR₁₈ orO(CO)NHR₁₈;

[0015] R₄ and R₆ represent, independently, an alkyl radical, acycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also one of thearyl or aralkyl radicals optionally substituted on their aryl group byone or more radicals chosen from the alkyl, hydroxy or alkoxy radicals,

[0016] R₅ and R₇ represent, independently, a hydrogen atom, an alkylradical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also oneof the aryl or aralkyl radicals optionally substituted on their arylgroup by one or more radicals chosen from the alkyl, hydroxy or alkoxyradicals,

[0017] R₄ and R₅ being able to form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the additionalmembers being chosen from the —CR₈R₉—, —NR₁₀—, —O— and —S— radicals, itbeing understood however that it there can only be one member chosenfrom —O— or —S— in said heterocycle,

[0018] and R₆ and R₇ being able to form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the additionalmembers being chosen from the —CR₁₁R₁₂—, —NR₁₃—, —O— and —S— radicals,it being understood however that there can only be one member chosenfrom —O— or —S— in said heterocycle,

[0019] R₈, R₁₀, R₁₁ and R₁₃ represent, independently each time they areinvolved, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkylradical,

[0020] R₉ and R₁₂ representing, independently each time they areinvolved, a hydrogen atom or each of R₉ and R₁₂ being able to formrespectively together with R₈ and R₁₁ an —O—(CH₂)₂—O— radical attachedon either side to the carbon atom which carries them, such a radicalonly being present however once at most per NR₄R₅ or NR₆R₇ radical,represent, independently each time they are involved, a hydrogen atom oran alkyl radical;

[0021] R₁₄ represents an alkyl, cycloalkyl or adamantyl radical or oneof the aryl, heteroaryl, aralkyl or heteroaralkyl radicals optionallysubstituted on their aryl or heteroaryl group by one or more radicalschosen from a halogen atom and the alkyl, haloalkyl, nitro, hydroxy,alkoxy, alkylthio or phenyl radicals,

[0022] or also R₁₄ is such that R₁₄—COOH represents a natural amino acidor the optical enantiomer of such an amino acid;

[0023] R₁₅, R₁₆ and R₁₇ represent, independently, an alkyl radical or aphenyl radical;

[0024] R₁₈ represents an alkyl, cycloalkyl or adamantyl radical or oneof the aryl, heteroaryl, aralkyl or heteroaralkyl radicals optionallysubstituted on their aryl or heteroaryl group by one or more radicalschosen from a halogen atom and the alkyl, haloalkyl, nitro, hydroxy,alkoxy, alkylthio or phenyl radicals;

[0025] it being understood however that when the compounds correspond togeneral sub-formula (I)₂, then R₁ does not represent a hydrogen atom;

[0026] or the salts of the latter.

[0027] By alkyl, unless otherwise specified, is meant a linear orbranched alkyl radical containing 1 to 12 carbon atoms, and preferably 1to 6 carbon atoms. By cycloalkyl, unless otherwise specified, is meant amonocyclic carbon system containing 3 to 7 carbon atoms. By haloalkyl,is meant an alkyl radical at least one of the hydrogen atoms (andoptionally all) of which is replaced by a halogen atom. By carbocyclicor heterocyclic aryl, unless otherwise specified, is meant a carbocyclicor heterocyclic system comprising one to three condensed rings at leastone of which is an aromatic ring, a system being referred to asheterocyclic when at least one of the rings comprising it contains oneor more heteroatoms (O, N or S). By aryl, unless otherwise specified, ismeant a carbocyclic aryl radical. By heteroaryl is meant a heterocyclicaryl radical. By haloalkyl, is meant an alkyl radical at least one ofthe hydrogen atoms (and optionally all) of which is replaced by ahalogen atom. Finally, by halogen atom is meant the fluorine, chlorine,bromine or iodine atoms.

[0028] By alkoxy, hydroxyalkyl, cycloalkylalkyl, aralkyl andheteroaralkyl radicals, is meant respectively the alkoxy, hydroxyalkyl,cycloalkylalkyl and aralkyl radicals the alkyl, cycloalkyl, aryl andheteroaralkyl radicals of which have the meanings indicated previously.

[0029] By natural amino acid, is understood valine (Val), leucine (Leu),isoleucine (Ile), methionine (Met), phenylalanine (Phe), asparagine(Asn), glutamic acid (Glu), glutamine (Gln), histidine (His), lysine(Lys), arginine (Arg), aspartic acid (Asp), glycine (Gly), alanine(Ala), serine (Ser), threonine (Thr), tyrosine (Tyr), tryptophane (Trp),cysteine (Cys) or proline (Pro).

[0030] By linear or branched alkyl having 1 to 6 carbon atoms, is meantin particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. By alkoxy, is meant in particular the methoxy, ethoxy andisopropoxy radicals, and in particular the methoxy and ethoxy radicals.By cycloalkyl is meant in particular the cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl radicals. By haloalkyl is meant in particularthe trifluoromethyl radical. By carbocyclic aryl is meant in particularthe phenyl, naphthyl and phenanthryl radicals, preferably the phenyl andnaphthyl radicals and more preferentially the phenyl radical. Byheterocyclic aryl is meant in particular the pyrrolyl, furanyl,benzofuranyl, thienyl, benzothienyl, pyridyl, pyrimidinyl, triazinyl,imidazolyl, oxazolyl, thiazolyl, indolyl and quinolyl radicals, andpreferably the furanyl, benzofuranyl, thienyl and benzothienyl radicals.By aralkyl is meant in particular a phenalkyl radical, and preferablythe benzyl radical. By heteroaralkyl is meant in particular athienylalkyl, furanylalkyl, pyrrolylalkyl and thiazolylalkyl radical(the alkyl radical of said radicals being preferably a methyl radical),and preferably a thienylalkyl radical (preferably thienylmethyl).

[0031] A compound of general formula (I) having at least one of thefollowing characteristics is preferred:

[0032] the compound corresponds to general sub-formula (I)₁;

[0033] R₁ represents a hydrogen atom or an NR₄R₅ radical;

[0034] R₂ represents an NR₆R₇ radical;

[0035] R₃ represents OH, or an O(CO)R₁₄, OSiR₁₅R₁₆R₁₇ or O(CO)NHR₁₈radical.

[0036] More preferentially, a compound of general formula (I) will besuch that it has at least one of the following characteristics:

[0037] the compound corresponds to general sub-formula (I)₁;

[0038] R₁ represents a hydrogen atom;

[0039] R₂ represents an NR₆R₇ radical;

[0040] R₃ represents AN O(CO)R₁₄, OSiR₁₅R₁₆R₁₇ or O(CO)NHR₁₈ radical.

[0041] Quite particularly, a compound of general formula (I) is suchthat it has at least one of the following characteristics:

[0042] the compound corresponds to general sub-formula (I)₁;

[0043] R₁ represents a hydrogen atom;

[0044] R₂ represents an NR₆R₇ radical and preferably an NR6R₇ radical inwhich R₆ and R₇ are chosen independently from a hydrogen atom and analkyl radical;

[0045] R₃ represents an O(CO)R₁₄, OSiR₁₅R₁₆R₁₇ or O(CO)NHR₁₈ radical.

[0046] Moreover, R₂ will quite preferentially represent an NR₆R₇radicalin which R₆ and R₇ are alkyl radicals, and in particular an NR₆R₇radical in which R₆ and R₇ are methyl radicals. R₃ will quitepreferentially represent an O(CO)NHR₁₈ radical.

[0047] Preferably also, R₄ will represent an alkyl or aralkyl radical,and R₅ will represent a hydrogen atom or an alkyl radical, or also R₄and R₅ will form together with the nitrogen atom which carries them aheterocycle with 5 to 7 members, the additional members being chosenfrom the —CR₈R₉—, —NR₁₀—, —O— and —S— radicals. Preferably, R₈ willrepresent, independently each time it is involved, a hydrogen atom or analkyl radical (and preferably a hydrogen atom) and R₉ will represent,independently each time it is involved, a hydrogen atom. Preferably, R₁₀will represent, independently each time it is involved, a hydrogen atomor an alkyl radical.

[0048] Preferably also, R₆ will represent an alkyl or aralkyl radical,and R₇ will represent a hydrogen atom or an alkyl radical, or also R₆and R₇ will form together with the nitrogen atom which carries them aheterocycle with 5 to 7 members, the additional members being chosenfrom the —CR₁₁R₁₂—, —NR₁₃—, —O— and —S— radicals. Preferably, R₁₁ willrepresent, independently each time it is involved, a hydrogen atom or analkyl or alkoxycarbonyl radical (and preferably a hydrogen atom) or alsoR₁₁ and R₁₂ will represent, once together, an —O—(CH₂)₂—O— radicalattached on either side to the carbon atom which carries it. Preferably,R₁₃ will represent, independently each time it is involved, a hydrogenatom or an alkyl radical.

[0049] Moreover, R₁₄ will preferably represent an alkyl or cycloalkylradical, or one of the aryl or heteroaryl radicals optionallysubstituted by a halogen atom or a haloalkyl or phenyl radical. Morepreferentially, R₁₄ will represent a cycloalkyl radical or one of thearyl or heteroaryl radicals optionally substituted by a halogen atom ora haloalkyl radical. In a more preferred manner, R₁₄ will represent acyclohexyl radical or one of the phenyl, thienyl or benzothienylradicals optionally substituted by a halogen atom.

[0050] Finally, R₁₅, R₁₆ and R₁₇ will preferably represent alkylradicals. In a particularly preferred manner, one of the R₁₅, R₁₆ andR₁₇ radicals will represent a tert-butyl radical and the other two willrepresent methyl radicals.

[0051] Finally, R₁₈ will preferably represent an alkyl, cycloalkyl oradamantyl radical, or one of the aryl or heteroaryl radicals optionallysubstituted by a halogen atom or an alkyl, haloalkyl, alkoxy, alkylthioor phenyl radical. More preferentially, R₁₈ will represent a cycloalkylradical or one of the aryl or heteroaryl radicals optionally substitutedby an alkyl, alkoxy or alkylthio radical. Still more preferably, R₁₈will represent one of the phenyl, thienyl or benzothienyl radicalsoptionally substituted by an alkyl, alkoxy or alkylthio radical.

[0052] Moreover, when R₄ and R₅ form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the NR₄R₅ radicalpreferably represents one of the pyrrolyl, piperidyl, piperazinyl,morpholinyl or thiomorpholinyl radicals optionally substituted by analkyl radical (the latter being preferably a methyl or ethyl radical,and more preferentially a methyl radical) on one of its carbon ornitrogen atoms, or by an —O—(CH₂)₂—O— radical attached on either side toa carbon atom. More preferentially, when R₄ and R₅ form together withthe nitrogen atom which carries them a heterocycle with 5 to 7 members,the NR₄R₅ radical will represent one of the pyrrolyl, piperidyl,piperazinyl, morpholinyl or thiomorpholinyl radicals optionallysubstituted by an alkyl radical (the latter being preferably a methylradical) on one of its carbon or nitrogen atoms.

[0053] Similarly, when R₆ and R₇ form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the NR₆R₇ radicalpreferably represents one of the pyrrolyl, piperidyl, piperazinyl,morpholinyl or thiomorpholinyl radicals optionally substituted by analkyl radical (the latter preferably being a methyl or ethyl radical,and more preferentially a methyl radical) on one of its carbon ornitrogen atoms, or by an —O—(CH₂)₂—O— radical attached on either side toa carbon atom. More preferentially, when R₆ and R₇ form together withthe nitrogen atom which carries them a heterocycle with 5 to 7 members,the NR₆R₇ radical will represent one of the pyrrolyl, piperidyl,piperazinyl, morpholinyl or thiomorpholinyl radicals optionallysubstituted by an alkyl radical (the latter preferably being a methylradical) on one of its carbon or nitrogen atoms.

[0054] The invention relates in particular to the following compoundsdescribed in the examples:

[0055] 12-diisopropylaminomethyl-7-methyl-3,6,10,15-tetraoxapentacyclo[12.2.1.0^(2,4).0^(5,7).0^(9,13)]heptadec-1(17)-ene-11,16-dione;

[0056]12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0057]12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8.10)]hexadec-13(16)-ene-4,14-dione;

[0058]11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0059]12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0060]11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0061]11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0062] -ethyl1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-12-yl]-4-piperidinecarboxylate;

[0063]12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6)0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0064]11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0065]12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0066]11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0067]11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0068]3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate;

[0069]3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene;

[0070] ethyl3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcarbonate;

[0071]11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0072]11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0073]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylbenzoate;

[0074]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate

[0075]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate;

[0076]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate;

[0077]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylheptanoate;

[0078]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-(trifluoromethyl)benzoate;

[0079]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate;

[0080]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate;

[0081]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl1-benzothiophene-2-carboxylate;

[0082]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-furoate;

[0083]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl5-nitro-2-furoate;

[0084]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thienylacetate;

[0085]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylphenoxyacetate;

[0086]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl4-tert-butylphenylcarbamate;

[0087]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-2-ylcarbamate;

[0088]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-methoxyphenylcarbamate;

[0089]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl 2(methylthio)phenylcarbamate;

[0090]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate;

[0091]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylcarbamate;

[0092]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylcarbamate;

[0093]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-ylN-(ter-butoxycarbonyl)glycinate;

[0094]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl thien-3-ylacetate;

[0095]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylacetate;

[0096]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthiophene-3-carboxylate;

[0097]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl5-phenylthien-2-ylcarbamate;

[0098]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-adamantylcarbamate;

[0099]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-naphthylcarbamate;

[0100]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2-tert-butyl-6-methylphenylcarbamate;

[0101]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2,5-dimethoxyphenylcarbamate;

[0102] as well as their salts.

[0103] The invention quite particularly relates to the followingcompounds:

[0104]12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0105]11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;

[0106]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylbenzoate;

[0107]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate;

[0108]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6.)0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate;

[0109]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate;

[0110]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate;

[0111]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-1-yl1-benzothiophene-2-carboxylate;

[0112]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl4-tert-butylphenylcarbamate;

[0113]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate;

[0114] as well as their salts.

[0115] As regards the salts of compounds of general formula (I), themaleates, fumarates, methanesulphonates and hydrochlorides of compoundsof general formula (I) are preferred, and in particular those describedin the examples, namely:

[0116]11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniummaleate;

[0117]11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniumfumarate;

[0118]11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniummethanesulphonate;

[0119]11-{[tert-butyl(dimethyl)silyl]oxy}-12-(dimethylamino)-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dionehydrochloride

[0120]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate hydrochloride.

[0121] A subject of the invention is also the compounds of generalformula (I)′

[0122] corresponding to general sub-formulae (I)′, and (I)′₂

[0123] in which

[0124] R₁ represents a hydrogen atom or an SR₄ or NR₄R₅ radical;

[0125] R₂ represents SR₆ or NR₆R₇;

[0126] R₃ represents OH, O(CO)R₁₄, O(CO)OR₁₄, or OSiR₁₅R₁₆R₁₇;

[0127] R_(4,) and R₆ represent, independently, an alkyl radical, acycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also one of thearyl or aralkyl radicals optionally substituted on their aryl group byone or more radicals chosen from the alkyl, hydroxy or alkoxy radicals,

[0128] R₅ and R₇ represent, independently, a hydrogen atom, an alkylradical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also oneof the aryl or aralkyl radicals optionally substituted on their arylgroup by one or more radicals chosen from the alkyl, hydroxy or alkoxyradicals,

[0129] R₄ and R₅ being able to form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the additionalmembers being chosen from the —CR₈R₉—, —NR₁₀—, —O— and —S— radicals, itbeing understood however that there can only be one member chosen from—O— or —S— in said heterocycle,

[0130] and R₆ and R₇ being able to form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the additionalmembers being chosen from the —CR₁₁R₁₂—, —NR₁₃—, —O— and —S— radicals,it being understood however that there can only be one member chosenfrom —O— or —S— in said heterocycle,

[0131] R₈, R₁₀, R₁₁ and R₁₃ represent, independently each time they areinvolved, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkylradical,

[0132] R₉ and R₁₂ representing, independently each time they areinvolved, a hydrogen atom or each of R₉ and R₁₂ being able to formrespectively with R₈ and R₁₁ an —O—(CH₂)₂—O— radical attached on eitherside to the carbon atom which carries them, such a radical only beingpresent however once at most per NR₄R₅ or NR₆R₇ radical,

[0133] represent, independently each time they are involved, a hydrogenatom or an alkyl radical;

[0134] R₁₄ represents an alkyl or cycloalkyl radical or one of the aryl,heteroaryl, aralkyl or heteroaralkyl radicals optionally substituted ontheir aryl or heteroaryl group by one or more radicals chosen from ahalogen atom and the alkyl, haloalkyl, nitro, hydroxy or alkoxyradicals;

[0135] R₁₅, R₁₆ and R₁₇ represent, independently, an alkyl radical or aphenyl radical;

[0136] it being understood however that when the compounds correspond togeneral sub-formula (I)′₂, then R₁ does not represent a hydrogen atom;

[0137] or the salts of the latter.

[0138] A subject of the invention is also the compounds of generalformula (I)″

[0139] corresponding to the general sub-formulae (I)″₁ and (I)″₂

[0140] in which

[0141] R₁ represents a hydrogen atom or an SR₄ or NR₄R₅ radical;

[0142] R₂ represents SR₆ or NR₆R₇;

[0143] R₃ represents OH, O(CO)R₁₄, O(CO)OR₁₄, or OSiR₁₅R₁₆R₁₇;

[0144] R_(4,) R₅, R₆ and R₇ represent, independently, a hydrogen atom,an alkyl radical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical oralso one of the aryl or aralkyl radicals optionally substituted on theiraryl group by one or more radicals chosen from the alkyl, hydroxy oralkoxy radicals,

[0145] R₄ and R₅ can form together with the nitrogen atom which carriesthem a heterocycle with 5 to 7 members, the additional members beingchosen from the —CR₈R₉—, —NR₁₀—, —O— and —S— radicals, it beingunderstood however that only one member chosen from —O— or —S— can befound in said heterocycle,

[0146] and R₆ and R₇ can form together with the nitrogen atom whichcarries them a heterocycle with 5 to 7 members, the additional membersbeing chosen from the —CR₁₁R₁₂—, —NR₁₃—, —O— and —S— radicals, it beingunderstood however that only one member chosen from —O— or —S— can befound in said heterocycle,

[0147] R₈, R₁₀, R₁₁ and R₁₃ represent, independently each time they areinvolved, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkylradical,

[0148] R₉ and R₁₂ representing, independently each time they areinvolved, a hydrogen atom or each of R₉ and R₁₂ can form with R₈ and R₁₁respectively an —O—(CH₂)₂—O— radical attached on either side to thecarbon atom which carries it, such radical however only being present atmost once per NR₄R₅ or NR₆R₇ radical, represent, independently each timethey are involved, a hydrogen atom or an alkyl radical;

[0149] R₁₄, R₁₅, R₁₆ and R₁₇ represent, independently, a hydrogen atom,an alkyl radical or one of the aryl or aralkyl radicals optionallysubstituted on their aryl group by one or more radicals chosen from thealkyl, hydroxy or alkoxy radicals;

[0150] it being understood however that when the compounds correspond tothe general sub-formula (I)″₂, then R₁ does not represent a hydrogenatom;

[0151] or the salts of the latter.

[0152] The compounds of the present invention can inhibit abnormal cellproliferation in a patient, for example a mammal such as man, byadministration to this patient of a therapeutically effective quantityof a compound of general formula (I), (I)′ or (I)″ or of apharmaceutically acceptable salt of such a compound.

[0153] The compounds of general formula (I), (I)′ or (I)″ have ananti-tumoral activity. They can be used for the treatment of tumors in apatient by administration to said patient of a therapeutically effectivequantity of a compound of general formula (I), (I)′ or (I)″ or of apharmaceutically acceptable salt of such a compound. Examples of tumorsor cancers include cancers of the oesophagus, stomach, intestines,rectum, buccal cavity, pharynx, larynx, lung, colon, breast, cervixuteri, corpus endometrium, ovaries, prostate, testicles, bladder,kidneys, liver, pancreas, bone, connective tissues, skin, for examplemelanomas, eyes, brain and central nervous system, as well as cancer ofthe thyroid, leukemia, Hodgkin's disease, lymphomas other than those ofHodgkin's disease, multiple myelomas and others.

[0154] They can also be used for the treatment of parasitic infectionsby inhibition of the hemoflagellates (for example in trypanosomia orleishmania infections) or by inhibition of the plasmodia (such as forexample in malaria), but also the treatment of viral infections anddiseases.

[0155] These properties make the compounds of the invention suitable forpharmaceutical use. A subject of the invention is therefore also, asmedicaments, the compounds of general formula (I), (I)′ or (I)″described previously or their pharmaceutically acceptable salts. It alsorelates to pharmaceutical compositions containing these compounds ortheir pharmaceutically acceptable salts. A further subject of theinvention is the use of these compounds or their pharmaceuticallyacceptable salts in order to produce medicaments intended to inhibit DNApolymerases, and in particular to treat diseases due to abnormal cellproliferation (in particular cancer or atherosclerosis, benignhyperplasia of the prostate and fibroses), as well as viral diseases andparasitic diseases, in particular those caused by protozoans (forexample malaria) or protists (for example diseases caused by amoebae).Finally, the invention relates to the use of the compounds of generalformula (I), (I)′ or (I)″ described previously or their pharmaceuticallyacceptable salts for preparing a medicament intended to treat diseasesof bacterial origin.

[0156] By pharmaceutically acceptable salt is meant in particularaddition salts of inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or organicacids such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate.The salts formed from bases such as sodium or potassium hydroxide alsofall within the scope of the present invention, when they can be used.For other examples of pharmaceutically acceptable salts, reference canbe made to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

[0157] The pharmaceutical compositions containing a compound of theinvention can be in solid form such as, for example, powders, pills,granules, tablets, liposomes, gelatin capsules or suppositories. Thepills, tablets or gelatin capsules can be coated with a substancecapable of protecting the composition from the action of the gastricacid or the enzymes in the subject's stomach for a sufficient period oftime to allow this composition to pass undigested into the subject'ssmall intestine. The compound can also be administered locally, forexample at the precise location of a tumor. The compound can also beadministered according to a sustained release process (for example usinga sustained release composition or a perfusion pump). Appropriate solidsupports can be, for example, calcium phosphate, magnesium stearate,magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

[0158] The pharmaceutical compositions containing a compound of theinvention can also be presented in liquid form such as, for example,solutions, emulsions, suspensions or a sustained release formulation.Appropriate liquid supports can be, for example, water, organic solventssuch as glycerol or glycols such as polyethylene glycol, as well astheir mixtures, in varying proportions, in water.

[0159] The administration of a medicament according to the invention canbe carried out by topical, oral, parenteral route, by intramuscularinjection, etc.

[0160] The dose of a compound according to the present invention, to beprovided for the treatment of the diseases or disorders indicated above,varies according to the method of administration, the age and the bodyweight of the subject to be treated as well as the latter's state, andthe final decision is made by the attending doctor or veterinarysurgeon. Such a quantity determined by the attending doctor orveterinary surgeon is here referred to as “therapeutically effectivequantity”.

[0161] The same preferences as those indicated previously for thecompounds of general formula (I) are applicable mutatis mutandis to thecompounds of general formula (I)′ or (I)″, to the medicaments of generalformula (I), (1)′ or (I)″, to the pharmaceutical compositions containinga compound of general formula (I), (I)′ or (I)″ and to the uses of acompound of general formula (I), (I)′ or (I)″ for preparing medicaments.

[0162] According to the invention, the compounds of general formula (I),(I)′ or (I)″ can be prepared by the processes described hereafter.

[0163] Preparation of Compounds of General Formula (I), (I)′ or (I)″ andtheir Salts

[0164] Preparation of Compounds of General Sub-Formula (I)₁:

[0165] CASE 1: R₁═H:

[0166] The preparation of this type of compound is summarized in Diagram1 hereafter. The dihydromikanolide by adding a nucleophile such as aprimary or secondary amine HNR₆R₇, or also a thiol R₆SH in the presenceof a base, in an inert solvent such as tetrahydrofuran or acetone, at atemperature preferably comprised between 0° C. and 50° C., and morepreferentially at ambient temperature.

[0167] In the case where R₃ is not OH, the intermediate obtained istreated with one of the reagents of general formula R₁₄(CO)-Hal (or anequivalent reagent such as for example the anhydride (R₁₄(CO))₂O),R₁₈O(CO)-Hal, Hal-Si R₁₅R₁₆R₁₇ (Hal representing a halogen atom) orR₁₈—NCO in order to obtain the desired final compound. Generally, thisreaction is carried out in an aprotic solvent such as dichloromethane,trichloroethane, acetonitrile, tetrahydrofuran or toluene, at atemperature preferably comprised between 0° C. and 110° C. andoptionally in the presence of a base such as triethylamine or4-dimethylaminopyridine. These types of reaction are well known to aperson skilled in the art (who can in particular usefully consult thefollowing reference publication: Greene et al., “Protective groups inOrganic Synthesis”, 2nd edition, Wiley, New-York, 1991) owing to theirfrequent use for protecting an alcohol or amine function. For example,as regards the silylation reaction, this is generally carried out bytreatment of an alcoholic compound with a silyl chloride in the presenceof a base, in an aprotic solvent at a temperature comprised between 0°C. and 50° C..

[0168] An additional method for obtaining compounds with R₃═OCOR₁₄consists of treating the intermediate alcohol with the acid R₁₄—COOH inthe presence of a base, such as for example dimethylaminopyridine, and acoupling agent, such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl).

[0169] CASE 2: R₁═R₂≠H :

[0170] The compounds of formula (I)₁ in which R₁═R₂≠H and R₃ representsa hydroxyl group can be prepared from mikanolide by adding anucleophilic such as a primary or secondary amine HNR₄R₅, or also athiol R₄SH in the presence of a base, in an inert solvent such astetrahydrofuran or acetone, at a temperature preferably comprisedbetween 0° C. and 50° C., and more preferentially at ambienttemperature.

[0171] In the case where R₃ is not OH, a second reaction is carried outusing a compound of general formula R₁₄(CO)-Hal (or an equivalentreagent such as for example (R₁₄(CO))₂O), R₁₈O(CO)-Hal orHal-SiR₁₅R₁₆R₁₇ anhydride (Hal representing a halogen atom) or R₁₈—NCOin order to obtain the desired final compound. This reaction can becarried out in a manner analogous to that disclosed in CASE 1.

[0172] An additional method for obtaining compounds with R₃═OCOR₁₄consists of treating the intermediate alcohol with the acid R₁₄—COOH inthe presence of a base, such as for example dimethylaminopyridine, andof a coupling agent, such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl).

[0173] CASE 3: R₁≠H and R₁≠R₂:

[0174] In this case, the compound of general formula (I)₂ is subjectedto the same reactions as in CASE 1 in order to produce the desired finalcompound in which R₁≠R₂.

[0175] Preparation of Compounds of General Sub-Formula (I)₂:

[0176] The compounds of sub-formula (I)₂ can be prepared, Diagram 4,from mikanolide by adding a nucleophile such as a primary or secondaryamine HNR₆R₇, or also a thiol R₆SH in the presence of a base, in aninert solvent such as tetrahydrofuran or acetone, at a temperaturepreferably comprised between 0° C. and 50° C., and more preferentiallyat ambient temperature.

[0177] Salts of Compounds of General Formula (I):

[0178] Certain compounds of the invention can be prepared in the form ofpharmaceutically acceptable salts according to the usual methods. Asregards these salts, a person skilled in the art can usefully consultthe article by Gould et al., “Salt selection for basic drugs”, Int. J.Pharm. (1 986), 33, 201-217.

[0179] Unless otherwise specified, all the technical and scientificterms used here have the same meaning as that usually understood by anordinary specialist in the field to which this invention belongs.Similarly, all the publications, patent applications, all the patentsand all other references mentioned here are incorporated by way ofreference.

[0180] The following examples are presented in order to illustrate theabove procedures and should in no event be considered as a limit to thescope of the invention.

EXAMPLES

[0181] The nomenclature used for the examples in principle conforms withthe IUPAC standards. It was determined using the ACD/Name® software(version 4.53) for examples 1 to 36 and using the ACD/Name® software(version 5.00) for examples 37 to 52.

[0182] The numbering indicated in the figure below is used for examples1 to 36 as regards the positions of the substituents —CH₂—R₁, R₂ and R₃on the polycycles of general sub-formulae (I)₁ and (I)₂:

Example 1

[0183] 12-diisopropylaminomethyl-7-methyl-3.6,10,15-tetraoxapentacyclo[12.2.1.0^(2,4).0^(5,7).0^(9,13)]heptadec-1(17)-ene-11,16-dione:

[0184] Diisopropylamine (500 μmol; 70 μl) is added to a solution ofmikanolide (100 μmol; 29 mg) in acetone (1 ml). The reaction mass isstirred for 30 minutes at ambient temperature then the solvent iseliminated by evaporation under reduced pressure. The residue is takenup in ether, filtered and dried under vacuum. 10 mg of product isobtained in the form of a white powder.

[0185] NMR-¹H (DMSO): 0.90-1.30 (m, 15H); 1.85 (m, 2H); 2.15 (t, 2H);3.15-3.50 (m, 4H); 3.95 (s, 1H); 4.75 (m, 1H); 5.50 (s, 1H); 6.00 (s,1H); 6.25 (s, 1H); 7.60 (s, 1H).

Example 2

[0186]12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0187] A solution of dimethylamine (160 μmol; 80 μl; 2M in THF) is addedto a solution of mikanolide (30 μmol; 9 mg) in acetone (0.3 ml). Thereaction mass is stirred for 30 minutes at ambient temperature thenconcentrated under reduced pressure. The residue is taken up in ether,filtered and dried under vacuum. 6 mg of expected compound is obtainedin the form of a white powder.

[0188] NMR-¹H (DMSO): 1.11 (s, 3H); 1.94-1.97 (m, 2H); 2.20 (s, 6H);2.47 (s, 6H); 2.67 (m, 2H); 2.85 (t, 1H); 3.07 (d, 1H); 3.15 (m, 1H);3.52 (d, 1H); 3.63 (m, 1H); 4.62 (m, 1H); 5.36 (s, 1H); 5.47 (s, 1H);8.00 (s, 1H).

[0189] NMR-¹³C (DMSO): 20.68; 42.85; 43.37; 44.71; 45.92; 49.95; 57.84;58.24; 61.61; 62.97; 67.94; 77.09; 80.67; 131.46; 151.01; 172.03;174.98.

Example 3

[0190]12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0191] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 2. The expectedproduct is obtained in the form of a white powder.

[0192] NMR-¹H (DMSO): 1.12 (s, 3H); 1.96 (m, 2H); 2.10 (m, 1H); 2.15 (s,3H); 2.47 (m, 2H); 2.83 (d, 2H); 2.89 (d, 1H); 3.22 (d, 1H), 3.26 (m,1H); 3.58 (dd, 2H); 3.69 (m, 1H); 3.89 (d, 1H); 3.93 (s, 2H); 4.73 (m,1H); 5.47 (d, 1H); 5.52 (s, 1H); 7.23-7.40 (m, 10H); 8.10 (s, 1H).

[0193] NMR-¹³C (DMSO): 20.65; 39.08; 40.54; 42.09; 43.09; 43.52; 50.18;56.57; 57.85; 60.17; 61.14; 62.21; 62.33; 68.37; 77.22; 81.01; 126.07;128.30; 131.48; 138.88; 139.67; 150.35; 172.16; 175.18.

Example 4

[0194]11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0195] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 2. The expectedproduct is obtained in the form of a white powder.

[0196] NMR-¹H (DMSO): 1.13 (s, 3H); 1.85-2.10 (m, 2H); 2.36 (m, 2H);2.40 (m, 2H); 2.74 (m, 4H); 2.88 (t, 1H); 2.95 (m, 2H); 3.10 (d, 1H);3.24 (m, 1H); 3.50-3.70 (m, 10H); 4.64 (m, 1H); 5.49 (s, 1H); 5.50 (d,1H); 8.01 (s, 1H).

Example 5

[0197]12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0198] A solution of dimethylamine (500 μmol, 250 μl, 2M in THF) isadded to a solution of dihydromikanolide (100 μmol, 29 mg) in acetone (1ml). The reaction mass is stirred for 2 hours at ambient temperaturethen the solvent is eliminated by evaporation under reduced pressure.The residue is taken up in ether, filtered and dried under vacuum. 25 mgof product is obtained in the form of a white powder.

[0199] NMR-¹H (DMSO): 1.10 (s, 3H); 1.25 (d, 3H), 1.90 (dd, 1H); 1.99(t, 1H); 2.49 (s, 6H); 2.58 (t, 1H); 2.94 (m, 1H); 3.06 (d, 1H); 3.51(m, 1H); 3.63 (m, 1H); (m, 1H); 5.34 (s, 1H); 5.37 (d, 1H); 8.00 (s,1H).

Example 6

[0200] 11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniummaleate:

[0201] A solution of maleic acid (0.1 mmol; 11.6 mg) in acetone (0.5 ml)is added to a solution of the compound of Example 5 (0.1 mmol; 34 mg) inacetone (0.5 ml). The precipitate is filtered, washed with acetone anddried under reduced pressure. 24 mg of the expected product is obtainedin the form of a white powder. Melting point: 178.5° C.

[0202] NMR-¹H (DMSO): 1.09 (s, 3H); 1.28 (d, 3H); 1.94 (dd, 1H); 2.05(m, 1H); 2.63 (t, 1H); 2.70-3.70 (m, 9H); 3.79 (t, 1H); 4.38 (s, 1H);4.68 (m, 1H); 5.45 (s, 1H); 6.07 (s, 2H); 8.31 (s, 1H).

Example 7

[0203] 11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniumfumarate:

[0204] A solution of fumaric acid (0.1 mmol; 11.6 mg) in acetone (3 ml)is added to a solution of the compound of Example 5 (0.1 mmol; 34 mg) inacetone (0.5 ml). The precipitate is filtered, washed with acetone anddried under reduced pressure. 15 mg of the expected product is obtainedin the form of a white powder. Melting point: 159° C.

[0205] NMR-¹H (DMSO): 1.11 (s, 3H); 1.25 (d, 3H); 1.92 (dd, 1H); 2.02(m, 1H); 2.58 (t, 1H); 2.80-4.00 (m, 11H); 4.64 (m, 1H); 5.34 (s, 1H);6.61 (s, 2H); 8.01 (s, 1H).

Example 8

[0206] 11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-12-yl(dimethyl)ammoniummethanesulphonate:

[0207] A solution of methanesulphonic acid (0.1 mmol; 1 ml; 0.1N inacetone) is added to a solution of the compound of Example 5 (0.1 mmol;34 mg) in acetone (2 ml). The precipitate is filtered, washed withacetone and dried under reduced pressure. 24 mg of the expected productis obtained in the form of a white powder. Melting point: 220° C.

[0208] NMR-¹H (DMSO): 1.09 (s, 3H); 1.29 (d, 3H); 1.97 (dd, 1H); 2.07(m, 1H); 2.30 (s, 3H); 2.65 (t, 1H); 2.80-3.15 (m, 7H); 3.28 (d, 1H);3.85 (t, 1H); 4.66-4.72 (m, 2H); 5.49 (s, 1H); 6.94 (s, 1H); 8.44 (s,1H); 10.04 (s, 1H).

Example 9

[0209]11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0210] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder. Melting point: 210°C.

[0211] NMR-¹H (DMSO): 0.80-3.50 (m, 23H); 3.60-3.75 (m, 2H); 4.62 (m,1H); 5.32 (s, 2H); 8.01 (s, 1H).

Example 10

[0212]11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0213] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0214] NMR-¹H (DMSO): 1.12 (s, 3H); 1.25 (d, 3H); 1.69 (m, 4H); 1.91(dd, 1H); 2.00 (m, 1H); 2.60 (t, 1H); 2.80 (m, 4H); 2.95 (m, 1H); 3.02(d, 1H); 3.45 (s, 1H); 3.63 (m, 1H); 4.61 (m, 1H); 5.34 (s, 1H); 5.42(d, 1H); 7.97 (s, 1H).

Example 11

[0215] ethyl1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo111.2.1.0^(2,6)]hexadec-13(16)-ene-12-yl]-4-piperidinecarboxylate:

[0216] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0217] NMR-¹H (DMSO): 1.00-4.00 (m, 25H); 4.04 (q, 2H); 4.64 (m, 1H);5.35 (s, 1H); 5.48 (d, 1H); 8.07 (s,1H).

Example 12

[0218]12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0219] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0220] NMR-¹H (DMSO): 1.00-1.80 (m, 12H); 1.85-2.10 (m, 2H); 2.35-4.00(m, 6H); 4.63 (m, 1H); 5.33 (m, 2H); 7.00-7.20 (m, 5H); 8.03 (s, 1H).

Example 13

[0221]11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0222] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0223] NMR-¹H (DMSO): 1.11 (s, 3H); 1.26 (d, 3H); 1.35-1.70 (m, 6H);1.85-2.14 (m, 2H); 2.57-3.18 (m, 7H); 3.50-3.75 (m, 2H); 4.64 (m, 1H);5.34 (m, 2H); 8.04 (s, 1H).

Example 14

[0224] 12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0225] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0226] NMR-¹H (DMSO): 1.11 (s, 3H); 1.26 (d, 3H); 1.40-1.80 (m, 6H);1.85-2.05 (m, 2H); 2.58-4.00 (m, 17H); 4.67 (m, 1H); 5.37 (s, 1H); 5.44(d, 1H); 8.08 (s, 1H).

Example 15

[0227]11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0228] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 5. The expectedproduct is obtained in the form of a white powder.

[0229] NMR-¹H (DMSO): 1.10 (s, 3H); 1.25 (d, 3H); 1.89 (dd, 1H); 2.01(m, 1H); 2.61 (t, 1H); 2.75 (m, 2H); 3.95 (m, 3H); 3.08 (d, 1H);3.55-3.75 (m, 5H); 4.63 (1H); 5.33 (s, 1H); 5.54 (d, 1H); 8.04 (s, 1H).

Example 16

[0230]11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0231] Terbutyldimethylsilyl chloride (80 μmol, 12 mg) is added to asolution of the compound of Example 5 (80 μmol; 27 mg) and imidazole(160 μmol; 11 mg) in DMF (0.5 ml). The solution obtained is stirred for20 hours then the reaction mass is poured into water. The aqueous phaseis extracted twice with ethyl acetate, the organic phase is washed withwater then with a solution of sodium chloride. The organic phase isdried over magnesium sulphate, filtered then evaporated. The residue iseluted on silica with a mixture of isopropyl acetate and dichloromethane(20/80). 20 mg of product is obtained in the form of a white powder.

[0232] NMR-¹H (DMSO): 0.04 (s, 3H); 0.07 (s, 3H); 0.89 (s, 9H); 1.14 (s,3H); 1.25 (d, 3H); 1.90 (dd, 1H); 1.99 (dd, 1H); 2.48 (s, 6H); 2.63 (t,1H); 2.93-2.98 (m, 1H); 3.12 (d, 1H); 3.43 (m, 1H); 3.80 (m, 1H); 4.61(m, 1H); 5.36 (s, 1H); 8.03 (s, 1H).

Example 17

[0233]3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate:

[0234] Acetic anhydride (150 μmol; 15 μl) is added to a solution of thecompound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). Thesolution obtained is stirred for 20 hours then the reaction mass ispoured into water. The aqueous phase is extracted twice with ethylacetate and the organic phase obtained is washed with water then with asolution of sodium chloride. The organic phase is dried over magnesiumsulphate, filtered then evaporated. The residue is eluted on silica witha mixture of isopropyl acetate and dichloromethane (20/80). 16 mg ofproduct is obtained in the form of a white powder.

[0235] NMR-¹H (DMSO): 0.90 (d, 3H); 1.11 (s, 3H); 1.26 (d, 3H); 1.35 (m,1H); 1.60 (m, 2H), 1.94 (dd, 1H); 2.03 (d, 1H); 2.09 (s, 3H); 2.43 (t,1H); 2.60 (t, 1H); 2.98 (d, 1H); 2.94-3.05 (m, 2H); 3.36-3.45 (m, 4H);4.07 (d, 1H); 4.64 (dd, 1H); 4.70 (m, 1H); 5.38 (s, 1H); 8.12 (s, 1H).

Example 18

[0236]3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene:

[0237] Benzoyl chloride (400 μmol; 46 μl) is added to a solution of thecompound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). Thereaction mass is stirred for 2 hours then treated in the same manner asfor the preparation of the compound of Example 17. 25 mg of product isobtained in the form of a white powder. Melting point: 234° C.

[0238] NMR-¹H (DMSO): 0.73 (d, 3H); 1.18 (s, 3H); 1.25 (m, 1H); 1.27 (d,3H); 1.45-1.60 (m, 2H); 2.00 (dd, 1H); 2.10 (m, 1H); 2.65 (t, 1H);2.92-3.15 (m, 3H); 3.45 (m, 2H); 3.54 (d, 1H); 4.18 (d, 1H); 4.36 (t,1H); 4.74 (m, 1H); 4.95 (t, 1H); 5.41 (s, 1H); 7.58 (t, 2H); 7.70 (t,1H); 8.01 (d, 2H); 8.19 (s, 1H).

Example 19

[0239] ethyl3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcarbonate:

[0240] Ethyl chloroformate (300 ∥mol; 28 μl) is added to a solution ofthe compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). Thereaction mass is stirred for 2 hours then treated in the same manner asfor the preparation of the compound of Example 17. 20 mg of product isobtained in the form of a white powder.

[0241] NMR-¹H (DMSO): 0.88 (d, 3H); 1.10-1.40 (m, 12H); 1.59 (m, 2H);2.90−2.10 (m, 2H); 2.35-2.50 (m, 2H); 2.58 (t, 1H); 2.80 (d, 1H);2.95-3.07 (m, 2H); 3.40 (d, 1H); 4.11-4.25 (m, 3H); 4.43 (dd, 1H); 4.70(m, 1H); 5.39 (s, 1H); 8.13 (s, 1H).

Example 20

[0242]11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0243] 2-methyl-1-propanethiol (500 μmol; 54 μl) is added to a solutionof mikanolide (100 μmol; 30 mg) and dimethylaminopyridine (10 μmol; 1.2mg) in acetone (1 ml). The reaction mass is stirred for two hours atambient temperature then the solvent is evaporated off under reducedpressure. The residue is taken up in ether, the precipitate is filtered,washed with ether and dried under vacuum. 35 mg of product is obtainedin the form of a white powder.

[0244] NMR-¹H (DMSO): 0.96 (m, 12H); 1.15 (s, 3H); 1.77 (m, 2H); 1.93(d, 2H); 2.50 (m, 4H); 2.80-2.98 (m, 4H); 3.39 (m, 1H); 3.76 (m, 1H);4.07 (d, 1H); 4.62 (q, 1H); 5.52 (s, 1H); 5.62 (s, 1H); 8.06 (s, 1H).

Example 21

[0245]11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione:

[0246] 2-methyl-1-propanethiol (500 μmol; 54 μl) is added to a solutionof dihydromikanolide (100 μmol; 30 mg) and dimethylaminopyridine (10μmol; 1.2 mg) in acetone (1 ml). The reaction mass is stirred for twohours at ambient temperature then the solvent is evaporated off underreduced pressure. The residue is taken up in ether then the precipitateformed is filtered, washed with ether and dried under vacuum. 25 mg ofproduct is obtained in the form of a white powder.

[0247] NMR-¹H (DMSO): 0.96 (t, 6H); 1.13 (s, 3H); 1.25 (d, 3H); 1.78 (m,1H); 1.89 (dd, 1H); 2.00 (t, 1H); 2.48 (m, 2H); 2.62 (t, 1H); 2.82 (d,1H), 2.98 (m, 1H); 3.78 (m, 1H); 4.07 (d, 1H); 4.57 (m, 1H); 5.40 (s,1H); 5.61 (d, 1H); 8.06 (s, 1H).

Example 22

[0248]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylbenzoate:

[0249] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0250] NMR-¹H (DMSO):1.21 (s, 3H); 1.28 (d, 3H); 1.98 (dd, 1H); 2.08 (t,1H); 2.48 (s, 6H); 2.66 (t, 1H); 3.01 (m, 1H); 3.51 (d, 1H); 4.04 (d,1H); 4.71 (m, 1H); 5.06 (dd, 1H); 4.43 (s, 1H); 7.58 (m, 2H); 7.70 (t,1H); 8.01 (d, 2H); 8.20 (s, 1H).

Example 23

[0251]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate:

[0252] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 17. The expectedproduct is obtained in the form of a white powder.

[0253] NMR-¹H (DMSO):1.14 (s, 3H); 1.26 (d, 3H); 1.94 (dd, 1H); 2.05 (t,1H); 2.08 (s, 3H); 2.45 (s, 6H); 2.62 (t, 1H); 3.97 (m, 1H); 3.32 (m,1H); 3.90 (d, 1H); 4.68 (m, 1H); 4.78 (m, 1H); 5.39 (s, 1H); 8.12 (s,1H).

Example 24

[0254]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate:

[0255] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0256] NMR-¹H (DMSO): 1.14 (s, 3H); 1.26 (d, 3H); 1.08-1.48 (m, 5H);1.58 (m, 1H); 1.68 (m, 2H); 1.84 (t, 2H); 1.93 (dd, 1H); 2.03 (t, 1H);2.37 (m, 1H); 2.44 (s, 6H); 2.61 (t, 1H); 2.98 (m, 1H); 3.32 (t, 1H);3.87 (d, 1H); 4.66 (m, 1H); 4.77 (dd, 1H); 5.40 (s, 1H); 8.12 (s, 1H).

Example 25

[0257]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate:

[0258] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0259] NMR-¹H (DMSO): 1.20 (s, 3H); 1.28 (d, 3H); 1.97 (dd, 1H); 2.08(t, 1H); 2.46 (s, 6H); 2.65 (t, 1H); 3.00 (m, 1H); 3.50 (d, 1H); 4.04(d, 1H); 4.71 (m, 1H); 5.04 (dd, 1H); 5.43 (s, 1H); 7.41 (t, 2H); 8.06(dd, 2H); 8.20 (s, 1H).

Example 26

[0260]11-{[tert-butyl(dimethyl)silyl]oxy}-12-(dimethylamino)-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dionehydrochloride:

[0261] A solution of hydrochloric acid (0.3 mmol; 0.3 ml; 1N in ether)is added to a solution of the compound of Example 16 (0.22 mmol; 100 mg)in acetone (2 ml). The precipitate is filtered, washed with a littleacetone, with ether and dried under reduced pressure. 70 mg of theexpected product is obtained in the form of a white powder.

[0262] NMR-¹H (DMSO): 0.14 (d, 6H); 0.90 (s, 9H); 1.15 (s, 3H); 1.27 (d,3H); 1.85 (dd, 1H); 2.05 (t, 1H); 2.72 (t, 1H); 2.90-3.25 (m, 7H); 3.72(m, 1H); 3.93 (m, 1H); 4.76 (m, 2H); 5.46 (s, 1H); 8.70 (d, 1H); 11.64(s, 1H).

Example 27

[0263]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylheptanoate:

[0264] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0265] NMR-¹H (DMSO): 0.86 (t, 3H); 1.14 (s, 3H); 1.20-1.35 (m, 9H);1.55 (m, 2H); 1.95 (dd, 1H); 2.02 (t, 1H); 2.35 (t, 2H); 2.44 (s, 6H);2.61 (t, 1H); 2.96 (m, 1H); 3.33 (t, 1H); 3.89 (d, 1H); 4.68 (m, 1H);4.77 (dd, 1H); 5.40 (s, 1H); 8.12 (s, 1H).

Example 28

[0266]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-(trifluoromethyl)benzoate:

[0267] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0268] NMR-¹H (DMSO):1.21 (s, 3H); 1.28 (d, 3H); 2.01 (dd, 1H); 2.06 (t,1H); 2.48 (s, 6H); 2.66 (t, 1H); 3.00 (m, 1H); 3.55 (d, 1H); 4.09 (d,1H); 4.73 (m, 1H); 5.04 (dd, 1H); 5.44 (s, 1H); 7.96 (d, 2H); 8.19 (d,2H); 8.21 (s, 1H).

Example 29

[0269]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate:

[0270] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0271] NMR-¹H (DMSO): 1.20 (s, 3H); 1.27 (d, 3H); 1.99 (m, 1H); 2.07 (t,1H); 2.49 (s, 6H); 2.65 (t, 1H); 3.00 (m, 1H); 3.47 (d, 1H); 4.00 (d,1H); 4.70 (m, 1H); 5.01 (dd, 1H); 5.43 (s, 1H); 7.26 (t, 1H); 7.87 (d,1H); 8.01 (dd, 1H); 8.18 (s, 1H).

Example 30

[0272]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate:

[0273] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0274] NMR-¹H (DMSO): 1.00 (s, 9H); 1.15 (s, 3H); 1.26 (d, 3H); 1.94(dd, 1H); 2.03 (t, 1H); 2.24 (dd, 2H); 2.45 (s, 6H); 2.62 (t, 1H); 2.98(m, 1H); 3.32 (d, 1H); 3.86 (d, 1H); 4.65 (m, 1H); 4.81 (dd, 1H); 5.40(s, 1H); 8.12 (s, 1H).

Example 31

[0275]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl1-benzothiophene-2-carboxylate:

[0276] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0277] NMR-¹H (DMSO): 1.22 (s, 3H); 1.28 (d, 3H); 2.01 (dd, 1H); 2.08(m, 1H); 2.50 (s, 6H); 2.66 (t, 1H); 3.00 (m, 1H); 3.52 (d, 1H); 4.05(d, 1H); 4.71 (m, 1H); 5.06 (dd, 1H); 5.44 (s, 1H); 7.50 (t, 1H); 7.56(t, 1H); 8.09 (t, 2H); 8.21 (s, 1H); 8.27 (s, 1H).

Example 32

[0278]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-furoate:

[0279] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0280] NMR-¹H (DMSO): 1.19 (s, 3H); 1.27 (d, 3H); 1.97 (dd, 1H); 2.07(t, 1H); 2.47 (s, 6H); 2.64 (t, 1H); 3.00 (m, 1H); 3.46 (d, 1H); 4.00(d, 1H); 4.70 (dd, 1H); 5.43 (s, 1H); 6.72 (d, 1H); 7.36 (d, 1H); 8.03(s, 1H); 8.18 (s, 1H).

Example 33

[0281]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl5-nitro-2-furoate:

[0282] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0283] NMR-¹H (DMSO): 1.19 (s, 3H); 1.28 (d, 3H); 1.98 (dd, 1H); 2.08(t, 1H); 2.45 (s, 6H); 2.64 (t, 1H); 3.00 (m, 1H); 3.53 (d, 1H); 4.08(d, 1H); 4.72 (m, 1H); 4.97 (dd, 1H); 5.44 (s, 1H); 7.65 (d, 1H); 7.80(d, 1H); 8.21 (s, 1H).

Example 34

[0284]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl 2-thiophenecarboxylatehydrochloride:

[0285] A solution of hydrochloric acid (0.8 mmol; 0.8 ml; 1N in ether)is added to a solution of the compound of Example 29 (0.44 mmol; 196 mg)in acetone (4 ml). The precipitate is filtered, washed with a littleacetone, with ether and dried under reduced pressure. 180 mg of theexpected product is obtained in the form of a white powder.

[0286] NMR-¹H (DMSO): 1.23 (s, 3H); 1.29 (d, 3H); 1.90 (dd, 1H); 2.13(t, 1H); 2.76 (t, 1H); 2.85-3.25 (m, 7H); 3.95 (m, 1H); 4.78 (m, 1H);5.02 (m, 1H); 5.38 (m, 1H); 5.51 (s, 1H); 7.29 (t, 1H); 7.97 (s, 1H);8.08 (d, 1H); 8.86 (s, 1H); 12.12 (s, 1H).

Example 35

[0287]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thienylacetate:

[0288] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0289] NMR-¹H (DMSO): 1.14 (s, 3H); 1.26 (d, 3H); 1.94 (dd, 1H); 2.04(m, 1H); 2.38 (s, 6H); 2.61 (t, 1H); 2.97 (m, 1H); 3.37 (d, 1H); 3.88(d, 1H); 4.00 (d, 2H); 4.68 (m, 1H); 4.78 (dd, 1H); 5.39 (s, 1H); 6.98(m, 2H); 7.43 (d, 1H); 8.12 (s, 1H).

Example 36

[0290]12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylphenoxyacetate:

[0291] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0292] NMR-¹H (DMSO): 1.23 (s, 3H); 1.35 (d, 3H); 2.04 (dd, 1H); 2.13(t, 1H); 2.58 (s, 6H); 2.67 (t, 1H); 3.06 (m, 1H); 3.48 (d, 1H); 4.08(d, 1H); 4.77 (m, 1H); 4.86 (m, 1H); 4.96 (dd, 2H); 5.50 (s, 1H); 7.05(m, 3H); 7.38 (m, 2H); 8.23 (s, 1H).

Example 37

[0293]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-cloxireno[f]oxacycloundecin-9-yl 4-tert-butylphenylcarbamate:

[0294] 4-terbutylphenylisocyanate (250 μmol; 44 mg) is added to asolution of the compound of Example 5 (200 μmol; 67 mg) in1,2-dichloroethane (10 ml). The solution obtained is stirred for 20hours at 60° C. before evaporating the solvent under reduced pressure.The residue is eluted on silica using a mixture of acetone anddichloromethane (20/80). The residue is taken up in ether, filtered anddried under vacuum. 36 mg of product is obtained in the form of a whitepowder.

[0295] NMR-¹H (DMSO): 1.18 (s, 3H); 1.25 (s, 9H); 1.27 (d, 3H); 1.95(dd, 1H); 2.08 (t, 1H); 2.48 (s, 6H); 2.64 (t, 1H); 2.98 (m, 1H); 3.37(m, 1H); 3.91 (d, 1H); 4.69 (m, 1H); 4.80 (dd, 1H); 5.40 (s, 1H); 7.29(d, 2H); 7.38 (d, 2H); 8.12 (s, 1H); 9.67 (s, 1H).

Example 38

[0296] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[loxacycloundecin-9-ylthien-2-ylcarbamate:

[0297] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0298] NMR-¹H (DMSO): 1.18 (s, 3H); 1.26 (d, 3H); 1.95 (m, 1H); 2.06 (m,1H); 2.48 (s, 6H); 2.64 (t, 1H); 2.97 (m, 1H); 3.36 (m, 1H); 3.90 (m,1H); 4.68 (m, 1H); 4.79 (m, 1H); 5.40 (s, 1H); 6.61 (s, 1H); 6.82 (s,1H); 6.94 (s, 1H); 8.13 (s, 1H); 10.78 (s, 1H).

Example 39

[0299] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-methoxyphenylcarbamate:

[0300] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0301] NMR-¹H (DMSO): 1.17 (s, 3H); 1.27 (d, 3H); 1.94 (dd, 1H); 2.05(t, 1H); 2.48 (s, 6H); 2.63 (t, 1H); 2.98 (m, 1H); 3.37 (m, 1H); 3.80(s, 3H); 3.87 (d, 1H); 4.68 (m, 1H); 4.80 (dd, 1H); 5.40 (s, 1H); 6.90(t, 1H); 7.02 (d, 1H); 7.09 (t, 1H); 7.59 (d, 1H); 8.12 (s, 1H); 8.59(s, 1H).

Example 40

[0302]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2(methylthio)phenylcarbamate:

[0303] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0304] NMR-¹H (DMSO): 1.17 (s, 3H); 1.27 (d, 3H); 1.95 (dd, 1H); 2.08(t, 1H); 2.40 (s, 3H); 2.48 (s, 6H); 2.63 (t, 1H); 2.98 (m, 1H); 3.37(s, 1H); 3.84 (d, 1H); 4.67 (m, 1H); 4.80 (dd, 1H); 5.39 (s, 1H);7.15-7.25 (m, 3H); 7.32 (t, 1H); 8.10 (s, 1H); 8.90 (s, 1H).

Example 41

[0305]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate:

[0306] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0307] NMR-¹H (DMSO): 1.17 (s, 3H); 1.27 (d, 3H); 1.35 (t, 3H); 1.95(dd, 1H); 2.05 (t, 1H); 2.48 (s, 6H); 2.63 (t, 1H); 2.98 (m, 1H); 3.34(m, 1H); 3.90 (d, 1H); 4.07 (q, 2H); 4.67 (m, 1H); 4.79 (dd, 1H); 5.40(s, 1H); 6.90 (t, 1H); 7.01 (d, 1H); 7.07 (t, 1H); 7.58 (d, 1H); 8.12(s, 1H); 8.46 (s, 1H).

Example 42

[0308]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylcarbamate:

[0309] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0310] NMR-¹H (DMSO): 1.18 (s, 3H); 1.27 (d, 3H); 1.95 (dd, 1H); 2.05(m, 1H); 2.48 (s, 6H); 2.64 (t, 1H); 2.98 (m, 1H); 3.36 (m, 1H); 3.90(d, 1H); 4.68 (m, 1H); 4.80 (dd, 1H); 5.40 (s, 1H); 7.04 (d, 1H); 7.22(s, 1H); 7.43 (t, 1H); 8.12 (s, 1H); 10.08 (s, 1H).

Example 43

[0311]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylcarbamate:

[0312] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 18. The expectedproduct is obtained in the form of a white powder.

[0313] NMR-¹H (DMSO): 1.20 (s, 3H); 1.28 (d, 3H); 1.98 (dd, 1H); 2.07(m, 1H); 2.48 (s, 6H); 2.65 (t, 1H); 2.98 (m, 1H); 3.40 (m, 1H); 3.97(d, 1H); 4.70 (m, 1H); 4.82 (dd, 1H); 5.40 (s, 1H); 7.40 (m, 2H); 7.65(s, 1H); 7.95 (d, 1H); 8.14 (m, 2H); 10.00 (s, 1H).

Example 44

[0314] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-ylN-(ter-butoxycarbonyl)glycinate:

[0315] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200μmol; 38 mg), N-terbutyloxycarbonylglycine (200 μmol; 35 mg),triethylamine (200 μmol; 28 μl) and dimethylaminopyridine (10 μmol; 3mg)are added to a solution of the compound of Example 5 (200 μmol; 60 mg)in dichloromethane (5 ml). The solution is stirred for three hours atambient temperature, poured into a solution of NaHCO₃ then extractedwith ethyl acetate. The organic phase is washed with water then with asaturated solution of sodium chloride before being dried over MgSO₄ andfiltered. The solvent is eliminated by distillation under reducedpressure. The residue is eluted on silica using a mixture of acetone anddichloromethane (40/60). The residue is taken up in ether, filtered anddried under vacuum. 25 mg of product is obtained in the form of a whitepowder.

[0316] NMR-¹H (DMSO): 1.15 (s, 3H); 1.26 (d, 3H); 1.39 (s, 9H); 1.92(dd, 1H); 2.05 (t, 1H); 2.43 (s, 6H); 2.62 (t, 1H); 2.98 (m, 1H); 3.35(t, 1H); 3.75 (t, 2H); 3.84 (d, 1H); 4.67 (m, 1H); 4.81 (dd, 1H); 5.40(s, 1H); 7.25 (t, 1H); 8.13 (s, 1H).

Example 45

[0317]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylacetate:

[0318] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 44. The expectedproduct is obtained in the form of a white powder.

[0319] NMR-¹H (DMSO): 1.14 (s, 3H); 1.26 (d, 3H); 1.94 (dd, 1H); 2.05(m, 1H); 2.37 (s, 6H); 2.61 (t, 1H); 2.97 (m, 1H); 3.33 (t, 1H); 3.77(s, 2H); 3.88 (d, 1H); 4.67 (m, 1H); 4.78 (dd, 1H); 5.39 (s, 1H); 7.04(d, 1H); 7.36 (s, 1H); 7.50 (t, 1H); 8.11 (s, 1H).

Example 46

[0320] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylacetate:

[0321] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 44. The expectedproduct is obtained in the form of a white powder.

[0322] NMR-¹H (DMSO): 1.13 (s, 3H); 1.25 (d, 3H); 1.94 (dd, 1H); 2.04(t, 1H); 2.26 (s, 6H); 2.60 (t, 1H); 2.96 (m, 1H); 3.32 (m, 1H); 3.88(d, 1H); 4.04 (s, 2H); 4.67 (m, 1H); 4.74 (dd, 1H); 5.38 (s, 1H); 7.40(m, 2H); 7.64 (s, 1H); 7.79 (d, 1H); 7.99 (d, 1H); 8.09 (s, 1H).

Example 47

[0323] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthiophene-3-carboxylate:

[0324] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 44. The expectedproduct is obtained in the form of a white powder.

[0325] NMR-¹H (DMSO): 1.19 (s, 3H); 1.27 (d, 3H); 1.97 (dd, 1H); 2.07(t, 1H); 2.48 (s, 6H); 2.65 (t, 1H); 2.99 (m, 1H); 3.46 (d, 1H); 3.98(s, 1H); 4.70 (m, 1H); 5.02 (m, 1H); 5.43 (s, 1H); 7.49 (s, 1H); 7.69(s, 1H); 8.18 (s, 1H); 8.40 (s, 1H).

Example 48

[0326] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl5-phenylthien-2-ylcarbamate:

[0327] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 37. The expectedproduct is obtained in the form of a white powder.

[0328] NMR-¹H (DMSO): 1.20 (s, 3H); 1.27 (d, 3H); 1.97 (dd, 1H); 2.03(t, 1H); 2.38 (s, 6H); 2.67 (m, 1H); 2.98 (m, 1H); 3.37 (d, 1H); 3.94(m, 1H); 4.69 (m, 1H); 5.41 (s, 1H); 6.60 (s, 1H); 7.22 (m, 2H); 7.36(t, 2H); 7.55 (d, 2H); 8.14 (s, 1H); 10.93 (s, 1H).

Example 49

[0329] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-adamantylcarbamate:

[0330] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 37. The expectedproduct is obtained in the form of a white powder.

[0331] NMR-¹H (DMSO): 1.14 (s, 3H); 1.26 (d, 3H); 1.60 (s, 6H);1.80-1.94 (m, 6H); 1.94-2.09 (m, 4H); 2.47 (s, 6H); 2.62 (t, 1H); 2.96(m, 1H); 3.21 (d, 1H); 3.38 (s, 1H); 3.76 (s, 1H); 4.64 (m, 2H); 5.37(s, 1H); 6.96 (s, 1H); 8.05 (s, 1H).

Example 50

[0332]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-naphthylcarbamate:

[0333] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 37. The expectedproduct is obtained in the form of a white powder.

[0334] NMR-¹H (DMSO): 1.20 (s, 3H); 1.28 (d, 3H); 1.96 (dd, 1H); 2.07(t, 1H); 2.48 (s, 6H); 2.66 (t, 1H); 3.01 (m, 1H); 3.37 (m, 1H); 3.95(d, 1H); 4.70 (m, 1H); 4.87 (dd, 1H); 5.42 (s, 1H); 7.38 (t, 1H); 7.46(t, 1H); 7.55 (d, 1H); 7.82 (m, 3H); 8.10 (s, 1H); 8.14 (s, 1H); 10.01(s, 1H).

Example 51

[0335] 8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2-tert-butyl-6-methylphenylcarbamate:

[0336] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 37. The expectedproduct is obtained in the form of a white powder.

[0337] NMR-¹H (DMSO): 1.14 (s, 3H); 1.20-1.42 (m, 12H); 1.92 (dd, 1H);2.05 (m, 1H); 2.25 (s, 3H); 2.52 (s, 6H); 2.62 (m, 1H); 2.95 (m, 1H);3.36 (m, 1H); 3.88 (m, 1H); 4.80-4.95 (m, 2H); 5.40 (s, 1H); 7.13 (m,2H); 7.22 (s, 1H); 8.13 (s, 1H); 8.69 (s, 1H).

Example 52

[0338]8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxa-cycloundecin-9-yl2,5-dimethoxyphenylcarbamate:

[0339] This compound is obtained by a procedure similar to thatdescribed for the synthesis of the compound of Example 37. The expectedproduct is obtained in the form of a white powder.

[0340] NMR-¹H (DMSO): 1.17 (s, 3H); 1.27 (d, 3H); 1.94 (dd, 1H); 2.06(m, 1H); 2.48 (s, 6H); 2.64 (t, 1H); 2.98 (m, 1H); 3.33 (m, 1H); 3.69(s, 3H); 3.76 (s, 3.89 (d, 1H); 4.68 (m, 1H); 4.80 (dd, 1H); 5.40 (s,1H); 6.63 (d, 1H); 6.94 (d, 1H); 7.32 (s, 1H); 8.12 (s, 1H); 8.58 (s,1H).

[0341] Pharmacological Study of the Compounds of the Invention

[0342] The usefulness of the compounds of the invention can bedemonstrated in particular by the effect of a treatment with thesecompounds on:

[0343] the incorporation of cytosine labelled with ³²P in a DNA fragmentin the presence of DNA polymerase of E. Coli (acellular system);

[0344] the incorporation of tritiated thymidine in the DNA of HT29 tumorcells in division over a period of 3 hours (cell system); and

[0345] the proliferation of two human cell lines Mia-Paca2 and DU145.

[0346] 1) Procedures

[0347] Cell Lines DU-145 (human prostate cancer cells), HT29 (cancer ofthe colon) and Mia-PaCa2 (human pancreatic cancer cells) were acquiredfrom the American Tissue Culture Collection (Rockville, Md., USA).

[0348] Incorporation of deoxycytidine 5′-[alpha³²P]-triphosphate into aDNA in the presence of DNA polymerase in an acellular system

[0349] Labelling of the DNA is carried out on a DNA fragment whichincorporates nucleotides by way of the activity of the DNA polymeraseenzyme. From these nucleotides, the dCTP is labelled with radioactivephosphorus (³²P).

[0350] Plasmidal DNA (pc DNA 3, invitrogen, Netherlands) is diluted to aconcentration of 2 ng in 45 μl of TE solution (10 mM Tris-HCl, pH 8, 1mM EDTA) and denatured by heating to 100° C. for 10 minutes before beingreplaced directly in ice. The denatured DNA is placed in the tube whichcontains the buffer solution of dATP, dGTP, dTTP, the Klenow DNApolymerase enzyme and the random primers (Rediprime II random primelabelling system, RPN 1633, RPN 1634, Amersham pharmacia biotech). 2 μlof Redivue deoxycytidine 5′-[alpha³²P]-triphosphate (250 μCi specificactivity Amersham, Orsay, France) is added to start the reaction. Thereaction is carried out in the presence or absence of the compound to betested for 10 minutes at 37°. The reaction is stopped by adding 5 μl ofEDTA (0.2M). The labelled DNA is recovered in 200 μL of isopropanolafter centrifugation for 10 minutes at 12,000 rpm then washed with 70%ethanol. After drying completely, the DNA is solubilized in 50 μl of TE.10 μL is counted in 5 ml of scintillator (Instagel plus andscintillation counter Packard, Rungis, France). The results areexpressed as a percentage of the inhibition of incorporation of thelabelled nucleotide in the sample with respect to the control: 100−[(DPMof the sample treated/control DPM)×100].

[0351] Incorporation of Thymidine Labelled with Tritium into DNA Cellsin Exponential Growth Phase

[0352] HT29 cells are seeded in 96-well plates (culturPlate-96, Packard,Rungis, France) (4000 cells per well) with the medium (DME, Gibco BRL,Cergy-Pontoise, France) complemented with 10% of foetal calf serum,Gibco BRL, Cergy-Pontoise, France). On day 3, the medium is removed andreplaced with medium containing the tritiated thymidine (5′-thymidineTRK.328, 1 mCi, 0.6 μCi/well, Amersham, Orsay, France) with or withoutthe compound. The treatments are carried out for 3 hours. The medium isthen removed and the cells are washed twice with 20 μl of PBS (GibcoBRL, Cergy-Pontoise, France). The lysis solution (SDS 1.25%, EDTA 5 mM)is added for 10 minutes at ambient temperature, then 75 μl ofscintillating liquid (microscint 40, Packard, Rungis, France) is added.The plates are read using Topcount (Packard, Rungis, France). Thesetests are carried out in duplicate and the results are expressed withrespect to the incorporation of the labelled nucleotide in the sampletreated with the compound over the incorporation of the labellednucleotide in the control sample (sample DPM/control DPM).

[0353] Measurement of Cell Proliferation

[0354] The cells placed in 80 μl of Dulbecco's modified Eagle medium(Gibco-BRL, Cergy-Pontoise, France) completed with 10% of foetal calfserum inactivated by heating (Gibco-BRL, Cergy-Pontoise, France), 50000units/l of penicillin and 50 mg/l streptomycin (Gibco-BRL,Cergy-Pontoise, France), and 2 mM of glutamine (Gibco-BRL,Cergy-Pontoise, France) were seeded on a 96-well plate on day 0. Thecells were treated on day 1 for 96 hours with increasing concentrationsof each of the compounds to be tested. At the end of the of this period,quantification of the cell proliferation is evaluated by a calorimetrictest based on the cleavage of the tetrazolium salt WST1 by mitochondrialdehydrogenases in viable cells leading to the formation of formazan(Boehringer Mannheim, Meylan, France). These tests are carried out induplicate with 8 determinations per concentration tested. The productsare solubilised in dimethylsulphoxide (DMSO) at 10⁻² M and finally usedin culture with 0.5% DMSO.

[0355] 2) Results

[0356] At a concentration of 100 μg/ml, the compound of Example 16, likedihydromikanolide, inhibits the activity of DNA polymerase in anacellular system (Table I). TABLE I % inhibition of incorporationDihydromikanolide 77 ± 11 Example 16 70 ± 8 

[0357] Moreover, the compound of Example 16, like dihydromikanolide,inhibits the incorporation of tritiated thymidine in the DNA of humanHT29 cells (Table II). TABLE II (sample dpm/control dpm) Concentrationμg/ml 100 50 25 Dihydromikanolide 0.14 0.22 0.98 Example 16 0.52 0.580.71

[0358] Finally, the compounds of Examples 1 to 3, 9, 16, 18, 22, 24 to32 and 39 to 43 inhibit the proliferation of DU-145 cell lines with anIC₅₀ inhibitory concentration lower than or equal to 30 μM, whereas thecompounds of Examples 1 to 10, 12, 16 to 20, 22, 24 to 37 and 39 to 44inhibit the proliferation of the Mia-Paca2 cell lines with an IC₅₀inhibitory concentration lower than or equal to 30 μM.

1. Compound of general formula (I)

corresponding to general sub-formulae (I)₁ and (I)₂

in which R₁ represents a hydrogen atom or an SR₄ NR₄R₅ radical; R₂represents SR₆ or NR₆R_(7;) R₃ represents OH, O(CO)R₁₄, OSiR₁₅R₁₆R₁₇,O(CO)OR₁₈ or O(CO)NHR₁₈; R₄ and R₆ represent, independently, an alkylradical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also oneof the aryl or aralkyl radicals optionally substituted on their arylgroup by one or more radicals chosen from the alkyl, hydroxy or alkoxyradicals, R₅ and R₇ represent, independently, a hydrogen atom, an alkylradical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also oneof the aryl or aralkyl radicals optionally substituted on their arylgroup by one or more radicals chosen from the alkyl, hydroxy or alkoxyradicals, R₄ and R₅ being able to form together with the nitrogen atomwhich carries them a heterocycle with 5 to 7 members, the additionalmembers being chosen from the —CR₈R₉—, —NR₁₀—, —O— and —S— radicals, itbeing understood however that it there can only be one member chosenfrom —O— or —S— in said heterocycle, and R₆ and R₇ being able to formtogether with the nitrogen atom which carries them a heterocycle with 5to 7 members, the additional members being chosen from the —CR₁₁R₁₂—,—NR₁₃—, —O— and —S— radicals, it being understood however that there canonly be one member chosen from —O— or —S— in said heterocycle, R₈, R₁₀,R₁₁ and R₁₃ represent, independently each time they are involved, ahydrogen atom or an alkyl, alkoxycarbonyl or aralkyl radical, R₉ and R₁₂representing, independently each time they are involved, a hydrogen atomor each of R₉ and R₁₂ being able to form respectively together with R₈and R₁₁ an —O—(CH₂)₂—O— radical attached on either side to the carbonatom which carries it, such a radical only being present however once atmost per NR₄R₅ or NR₆R₇ radical, represent, independently each time theyare involved, a hydrogen atom or an alkyl radical; R₁₄ represents analkyl, cycloalkyl or adamantyl radical or one of the aryl, heteroaryl,aralkyl or heteroaralkyl radicals optionally substituted on their arylor heteroaryl group by one or more radicals chosen from a halogen atomand the alkyl, haloalkyl, nitro, hydroxy, alkoxy, alkylthio or phenylradicals; or also R₁₄ is such that R₁₄—COOH represents a natural aminoacid or the optical enantiomer of such an amino acid; R₁₅, R₁₆ and R₁₇represent, independently, an alkyl radical or a phenyl radical; R₁₈represents an alkyl, cycloalkyl or adamantyl radical or one of the aryl,heteroaryl, aralkyl or heteroaralkyl radicals optionally substituted ontheir aryl or heteroaryl group by one or more radicals chosen from ahalogen atom and the alkyl, haloalkyl, nitro, hydroxy, alkoxy, alkylthioor phenyl radicals; it being understood however that when the compoundscorrespond to general sub-formula (I)₂, then R₁ does not represent ahydrogen atom; or a salt of a compound of general formula (I). 2.Compound according to claim 1, characterized in that it corresponds togeneral sub-formula (I), or is a salt of such a compound.
 3. Compoundaccording to claim 2, characterized in that: R₁ represents a hydrogenatom or an NR₄R₅ radical; R₂ representing an NR₆R₇ radical; R₃represents OH or an O(CO)R₁₄, OSiR₁₅R₁₆R₁₇ or O(CO)NHR₁₈ radical. 4.Compound according to claim 1, characterized in that it corresponds togeneral sub-formula (I)₂.
 5. Compound according to claim 1,characterized in that it is one of the following compounds:12-diisopropylaminomethyl-7-methyl-3,6,10,15-tetraoxapentacyclo[12.2.1.0^(2,4).0^(5,7).0^(9,13)]heptadec-1(17)-ene-1,16-dione;12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dion12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;ethyl1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-12-yl]-4-piperidinecarboxylate;12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene;ethyl3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcarbonate;11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-ylbenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-ylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylheptanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-(trifluoromethyl)benzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[1.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl1-benzothiophene-2-carboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl5-nitro-2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-yl2-thienylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-ylphenoxyacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl4-tert-butylphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-2-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-methoxyphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2(methylthio)phenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-ylN-(ter-butoxycarbonyl)glycinate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthiophene-3-carboxylate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl5-phenylthien-2-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-adamantylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-naphthylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2-tert-butyl-6-methylphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2,5-dimethoxyphenylcarbamate; or a salt of one of the latter.
 6. As amedicament, a compound of general formula (I) as defined in claim 1 or apharmaceutically acceptable salt of the latter.
 7. Medicament accordingto claim 6, characterized in that it is one of the following compounds:12-diisopropylaminomethyl-7-methyl-3,6,10,15-tetraoxapentacyclo[12.2.1.0^(2,4).0^(5,7).0^(9,13)]heptadec-1(17)-ene-11,16-dione;12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;ethyl1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-12-yl]-4-piperidinecarboxylate;12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclot11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene;ethyl3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcarbonate;11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-ylbenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8.10)]hexadec-13(16)-en-11-ylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylheptanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)9 hexadec-13(16)-en-11-yl 4-(trifluoromethyl)benzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl1-benzothiophene-2-carboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl5-nitro-2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2.6).0^(8,10)]hexadec-13(16)-en-11-yl2-thienylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylphenoxyacetate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl4-tert-butylphenylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-2-ylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-methoxyphenylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2(methylthio)phenylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-ylN-(ter-butoxycarbonyl)glycinate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylacetate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylacetate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthiophene-3-carboxylate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl5-phenylthien-2-ylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-adamantylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-naphthylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2-tert-butyl-6-methylphenylcarbamate;8-(dimethylamino)-3.10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2,5-dimethoxyphenylcarbamate; or a pharmaceutically acceptable salt ofone of the latter.
 8. Pharmaceutical composition containing, as activeingredient, a compound of general formula (I) as defined in claim 1 or apharmaceutically acceptable salt of the latter.
 9. Pharmaceuticalcomposition according to claim 8, characterized in that it contains, asactive ingredient, one of the following compounds:12-diisopropylaminomethyl-7-methyl-3,6,10,15-tetraoxapentacyclo[12.2.1.0^(2,4).0^(5,7).0^(9,13)]heptadec-1(17)-ene-11,16-dione;12-dimethylamino-3-dimethylaminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-benzyl(methyl)amino-3-benzyl(methyl)aminomethyl-11-hydroxy-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-8-methyl-12-morpholino-3-morpholinomethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-dimethylamino-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-(4-methylpiperidino)-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-pyrrolidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;ethyl1-[11-hydroxy-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-12-yl]-4-piperidinecarboxylate;12-(4-benzylpiperidino)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-piperidino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-11-hydroxy-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-3,8-dimethyl-12-morpholino-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-(tert-butyldimethylsiloxy)-12-dimethylamino-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylacetate;3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-11-phenylcarbonyloxy-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene;ethyl3,8-dimethyl-12-(4-methylpiperidino)-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcarbonate;11-hydroxy-12-isobutylsulphanyl-3-isobutylsulphanylmethyl-8-methyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;11-hydroxy-12-isobutylsulphanyl-3,8-dimethyl-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-ene-4,14-dione;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-ylbenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-ylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylcyclohexanecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-fluorobenzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-ylheptanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl4-(trifluoromethyl)benzoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-thiophenecarboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl3,3-dimethylbutanoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl1-benzothiophene-2-carboxylate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.0^(2,6).0^(8,10)]hexadec-13(16)-en-11-yl5-nitro-2-furoate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-yl2-thienylacetate;12-(dimethylamino)-3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo[11.2.1.02.6.08.10]hexadec-13(16)-en-11-ylphenoxyacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl4-tert-butylphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-2-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-methoxyphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2(methylthio)phenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-ethoxyphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[4oxacycloundecin-9-yl1-benzothien-3-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-ylN-(ter-butoxycarbonyl)glycinate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthien-3-ylacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-benzothien-3-ylacetate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-ylthiophene-3-carboxylate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl5-phenylthien-2-ylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl1-adamantylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro[3,2-c]oxireno[f]oxacycloundecin-9-yl2-naphthylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2-tert-butyl-6-methylphenylcarbamate;8-(dimethylamino)-3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo[3,2-c]oxireno[f]oxacycloundecin-9-yl2,5-dimethoxyphenylcarbamate; or a pharmaceutically acceptable salt ofone of the latter.
 10. Use of a compound of general formula (I) asdefined in claim 1 or a pharmaceutically acceptable salt of the latterfor preparing a medicament intended to inhibit DNA polymerases.
 11. Useof a compound of general formula (I) as defined in claim 1 or apharmaceutically acceptable salt of the latter for preparing amedicament intended to treat diseases due to abnormal cellproliferation.
 12. Use according to claim 11, characterized in that thedisease due to abnormal cell proliferation is cancer.
 13. Use accordingto claim 11, characterized in that the disease due to abnormal cellproliferation is chosen from atherosclerosis, benign hyperplasia of theprostate and fibroses.
 14. Use of a compound of general formula (I) asdefined in claim 1 or a pharmaceutically acceptable salt of the latterfor preparing a medicament intended to treat viral diseases.
 15. Use ofa compound of general formula (I) as defined in claim 1 or apharmaceutically acceptable salt of the latter for preparing amedicament intended to treat parasitic diseases.
 16. Use of a compoundof general formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt of the latter for preparing a medicament intended totreat diseases of bacterial origin.